Therapeutic vascularization to support repair of damaged salivary glands

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Project Summary Damage to salivary glands is a devastating condition – identification of therapies to promote regeneration of these important organs is imperative. Great progress is being made in engineering and transplantation of salivary gland epithelium. A major remaining hurdle in gland engineering is the need to establish a functional vasculature, which is essential for survival of any replacement tissue in vivo. In addition to essential support, therapeutic angiogenesis also stimulates healing of non-vascular tissue. This study will characterize methods of promoting vascularization in regenerating salivary gland tissues. Using mice as a pre-clinical model system, we will evaluate two distinct therapeutic approaches – individually and in combination – to promote vascularization and regeneration of damaged glands. One therapeutic approach involves implantation of an exogenous vascular cell milieu as a method to enhance formation of functional blood vessel networks. The other approach, which may be effective when used in conjunction with implanted cells, or on its own, will involve systemic delivery of a drug with potential to stimulate angiogenesis. The therapeutic potentials of the of the two approaches will be evaluated separately and in combination in vivo in mice in a biopsy wound healing model. Cellular and molecular events of vascular assembly associated with each therapy will be defined using cell culture assays in vitro. For implantation of vascular cells, we will use a cell milieu of stromal vascular fraction derived from adipose (AdSVF). The AdSVF cell milieu has real advantages as a cell source. It includes many cell types needed to form functional blood vessel networks (endothelial, pericytes, vascular smooth muscle, fibroblasts) it reduces inflammation to promote regeneration of parenchymal tissue, it is readily available for self-donation, and, importantly, has proven safe for clinical use. As an adjunct to implanted AdSVF, or as a stand-alone vascularizing therapeutic, we will also test the ability of a systemic pharmacologic agent Tazarotene to stimulate formation of functional vascular networks. Tazarotene is a synthetic retinoid. Its vascular promoting activity is consistent with the action of natural retinoids, including vitamin A and its derivative retinoic acid, which are essential for vascular assembly in vivo. This project will identify methods to promote functional vasculature in regenerating salivary glands. Resulting knowledge can be used to enhance success of therapies aimed at repairing salivary epithelium, thereby advancing the field toward developing effective therapies for patients suffering from salivary gland damage.